Schizophrenia: genes matter (even though inheritance might not)

A new study shows that schizophrenia is often associated with new mutations …

A large number of human disorders—autism and cancer among them—display a confusing pattern of inheritance. In some cases, they are clearly genetic, with frequent occurrences in individual families. But in others, new cases will appear in families that were otherwise unaffected.

Initially, this pattern was assumed to result from diseases that had multiple causes. But with some diseases, we've come to recognize that mutations (whether inherited or not) play a much larger role than expected. The latest disease to join this category is schizophrenia.

Schizophrenia is a behavioral disorder that follows the pattern of many others, including autism and dyslexia: in many cases, it runs in families, and these families have allowed us to identify mutations in key genes that are associated with the disorder. In many other instances, however, only a single individual in a family is affected, which suggests that environmental causes may play a key role in these cases.

In recent years, an alternative explanation has been proposed: mutations are nearly always important for these diseases, but the mutations aren't always inherited. This first became clear for cancer, where researchers realized that sporadic cases of the disease resulted from mutations that cells had picked up over the course of their history in the body (and that environmental influences act by altering the frequency of mutations). There's generally a substantial overlap between these sporadic mutations and the ones that are mutated in the cancer's heritable form.

But the cells that become cancerous often take decades of environmental insults to pick up mutations, which doesn't explain many behavioral disorders. These can have an early onset and may be associated with structural differences in the brain that arise early in development—potentially prior to birth. There doesn't seem to be the same sort of room for mutations in these cases. Plus, even if we suspected in the past that mutations were involved, we didn't have the technology to find them.

Better tools

Over the last few years, however, that last bit has changed. First, we developed the technology to screen the entire genome for what are called copy number variations (CNVs), areas where a section of a chromosome was duplicated or deleted. When we looked, we discovered that new CNVs—ones that weren't inherited from either parent—were more common in individuals with autism than in controls. These mutations seem to arise either in the production of eggs and sperm or in the first few cell divisions after fertilization, so they can cause effects as the brain develops.

Even as those results came in, technology continued to improve, and the new schizophrenia study takes advantage of a technique called whole exome sequencing. Instead of looking for large-scale changes like CNVs, exome sequencing focuses on small changes that take place in key areas: the one to two percent of the human genome that actually codes for proteins (this portion is contained in things called exons, hence the term "exome"). This can be sequenced using the same high-throughput machines that are being used to complete whole genomes and, because there's so much less DNA to sequence, it's possible to look at many more individuals.

Comparing exomes

That's precisely what the researchers behind the new study have done. They sequenced the entire exomes of 53 schizophrenia patients, along with the exomes of their parents, in families that have no wider history of the disease. Then, as controls, they sequenced similar trios in families that had no history of schizophrenia at all. (As part of this work, they actually identified some families that had new CNVs, but to keep them from confusing matters, didn't include them in the final analysis.)

With the sequencing done, the researchers looked over the results, trying to spot cases where an individual had a DNA sequence that wasn't present in either parent. In just over half the individuals with schizophrenia, the team was able to spot one or more of these differences, and most of are predicted to alter the function of the gene they reside in. In contrast, less than a third of the control cases seemed to have these new mutations, which were ten times less likely to alter any genes. At least one of the genes identified in the patient population had previously been associated with an inherited form of schizophrenia.

These results suggest that schizophrenia is generally caused by mutations, even in cases where the mutations haven't been inherited. This still leaves significant space for environmental influences, though; these could influence the occurrence of the disease by altering the mutation rate, for example. Schizophrenia is a complex disease, and environmental factors may also alter the timing of its onset and its progression afterwards.

The results clearly have significance beyond schizophrenia. Many other disorders, including ALS and dyslexia, show the same sort of pattern: a mix of inherited and sporadic cases. Autism and schizophrenia, by showing that mutations may underlie both types of case, may provide a model that helps us understand a wide variety of disorders.

I think the most interesting thing to me is that this likely means that families with incidence of the inherited disease can have children who will have "disinherited " the disease through the same mechanism of mutations.

It unfortunately doesn't explain why 9/10 of all people diagnosed with schizophrenia live below the poverty line, or why as a clinical psychologist working in a psychiatric inpatient unit, the majority of my clients diagnosed with schizophrenia have experienced sexual or physical childhood abuse, or ongoing social victimisation (an experience validated by corrolatory research). It still begs the question that even with some genetic links, how strong do social factors have to be before we stop referring to the schizophrenia 'disease', and understand it within its proper classification as a syndrome?

It unfortunately doesn't explain why 9/10 of all people diagnosed with schizophrenia live below the poverty line, or why as a clinical psychologist working in a psychiatric inpatient unit, the majority of my clients diagnosed with schizophrenia have experienced sexual or physical childhood abuse, or ongoing social victimisation (an experience validated by corrolatory research). It still begs the question that even with some genetic links, how strong do social factors have to be before we stop referring to the schizophrenia 'disease', and understand it within its proper classification as a syndrome?

It unfortunately doesn't explain why 9/10 of all people diagnosed with schizophrenia live below the poverty line, or why as a clinical psychologist working in a psychiatric inpatient unit, the majority of my clients diagnosed with schizophrenia have experienced sexual or physical childhood abuse, or ongoing social victimisation (an experience validated by corrolatory research). It still begs the question that even with some genetic links, how strong do social factors have to be before we stop referring to the schizophrenia 'disease', and understand it within its proper classification as a syndrome (a judgement made on grouping a set of behaviours used as a descriptive label, rather than an assumption of cause)?

It unfortunately doesn't explain why 9/10 of all people diagnosed with schizophrenia live below the poverty line, or why as a clinical psychologist working in a psychiatric inpatient unit, the majority of my clients diagnosed with schizophrenia have experienced sexual or physical childhood abuse, or ongoing social victimisation (an experience validated by corrolatory research). It still begs the question that even with some genetic links, how strong do social factors have to be before we stop referring to the schizophrenia 'disease', and understand it within its proper classification as a syndrome (a judgement made on grouping a set of behaviours used as a descriptive label, rather than an assumption of cause)?

Poverty has more to do with not being able to hold down a job, which is difficult for people who's functioning is impaired by hallucinations/delusions/disorganization/negative symptoms. I believe those with schizophrenia who experience abuse have much worse outcomes for dealing with their illness than those without, thus they end up in your inpatient unit. People with schizophrenia are vastly more likely to be victims of violent crime than people without mental illness.

Genetics produce a possibility, and social strife is often the trigger for it. Drugs are another trigger - I used to think I was being fed a bunch of propaganda when adults told me drugs can lead to schizophrenia... Yet at the moment I have two clients on my case load who's triggers were LSD/Ecstasy.

Poverty has more to do with not being able to hold down a job, which is difficult for people who's functioning is impaired by hallucinations/delusions/disorganization/negative symptoms. I believe those with schizophrenia who experience abuse have much worse outcomes for dealing with their illness than those without, thus they end up in your inpatient unit. People with schizophrenia are vastly more likely to be victims of violent crime than people without mental illness.

Yep, drawing some kind of cause and effect related to such issues are likely to be damned difficult.

If this isn't enough to cause some kind of mental illness, I don't know what is. The fact that it may have a genetic component associated with it is no surprise to me - diabetes works the same way; people have a genetic predisposition for diabetes, but it doesn't manifest itself until some outside stimulus (poor diet) triggers it.

And the last thing we need to spend money on is another study that does little more than prove the obvious. So many results of "scientific studies" I read about get me yelling "Well, DUH! I could-a told you that you moron!" at my computer screen.

A plea to scientists: Please to do not insult the intelligence of the average blog reader.

And the last thing we need to spend money on is another study that does little more than prove the obvious. So many results of "scientific studies" I read about get me yelling "Well, DUH! I could-a told you that you moron!" at my computer screen.

A plea to scientists: Please to do not insult the intelligence of the average blog reader.

Until the numbers and graphs are presented, any claim of "knowing" is simply speculation.

Hell, science is not so much about proving a claim as disproving it. Only by failing every conceivable way of disproving a claim have one "proven" it to be right.

To throw in a personal example related to cancer that illustrates the point, as a child I had Wilm's tumor which can run in families but is due to a double hit mutation 95% of the time. (Appologies if I get the latest biology wrong, I'm not a biologist). Wilm's tumor is a cancer of the kidney that only strikes children. It turns out it is due to a genetic error in the gene that tells undeveloped cells to turn into kidney cells, basically the regulator gene that switches cells into kidney cells is defective so they just keep growing instead of becoming kidney cells.

Almost everyone has two copies of this gene, and you only need one working copy. However, if you inherit only one working copy the chance of having a cell with a mutation in the good copy is quite high. So there are families in which Wilm's runs (one bad recessive copy), but the mortality of children prior to modern chemo was so high this is very rare—even with only one bad copy you are likely to have a single cell with a mutation and thus get Wilm's.

Most children who get Wilm's are victims of a double hit mutation—they inhereted two working copies of the gene, but one cell acquired mutations in both copies. So most cases are truly random. An interesting corollary is most of these people will not pass on Wilm's. Their germ cells have two working copies, it is only somewhere in the kidneys that two mutations accumulated.

It is very interesting if similar effects are appearing in mental ilness, as this had never occurred to me.

This is fantastic news! If this is true, then people of the future will get pre-mutation preventative care and post-mutation treatment starting shortly after fertilization. Couples may even receive treatment prior to conceiving. We also might be able to lock down the environmental insults that cause mutations. I'm not saying these disorders will go away, but reducing all mutation-triggered disorders at the source would be a huge step forward for medical science!

Ah, so it's not the vaccines in the children causing autism. Then it must be the vaccines that the adults had when they were children that's causing their children to get autism.

Seems like a good reason to get rid of all that old, vaccine infected sperm as frequently as possible.

Isn't it interesting how often people who distrust science still show up at the Doctor's office when they are ill? I wonder if there could be a market for Shamanic services? After-all, it's all 'just' a theory, right?

Ah, so it's not the vaccines in the children causing autism. Then it must be the vaccines that the adults had when they were children that's causing their children to get autism.

Seems like a good reason to get rid of all that old, vaccine infected sperm as frequently as possible.

Isn't it interesting how often people who distrust science still show up at the Doctor's office when they are ill? I wonder if there could be a market for Shamanic services? After-all, it's all 'just' a theory, right?

Maybe you hadn't heard of homeopaths. They do lots of business selling water.

Metaphysical wrote:"Genetics produce a possibility, and social strife is often the trigger for it. Drugs are another trigger - I used to think I was being fed a bunch of propaganda when adults told me drugs can lead to schizophrenia... Yet at the moment I have two clients on my case load who's triggers were LSD/Ecstasy".

Are you sure it was real LSD? From what I've read there are several LSD mimics in the street ( DOB, DOC, DOI and 2C-I). Assuming Ecstasy is benign (if it is ? / methylenedioxymethamphetamine by itself anyway) LSD can still illicit short term "fugue states" of psychosis in a very small portion (0.8%) of test subjects. Several of these special incidents might have been triggered by LSD accompanied by a tricyclic antidepressant (usually) or lithium salt. Non reversible chronic psychosis caused by LSD is supposed to be very rare; right? And even then a preschizophrenic disposition is probably manifest in the subject; right?. Your opinions please...

SORRY, THE COMMENT ABOUT THE CHILDREN MUST OF BEEN ABUSED IN SOME WAY ,WELL THATS IMPOSSIBLE IN MY FAMILY. I WORKED ONLY PART TIME , I HAD 3 KIDS WITH THE SCHIZOPHRENIA. I KEPT A GOOD EYE ON THEM . I WAS ALSO A PRESCHOOL TEACHER AND I KNEW HOW TO RAISE THEM RIGHT. I TOOK THEM TO WORK WITH ME ALSO, I HAD A GOOD EMPLOYER. THE 10 KIDS MY MOM HAD, NONE HAD SCHIZOPHRENIA BUT MINE . NO AUNTS OR UNCLES EITHER, NO COUSINS WHO CAN REALLY SAY WHAT HAPPEN , MAYBE GOD WANTED IT THAT WAY, NEVER THE LESS THERE ON THE MEDS AND SAPHRIS SEEMS TO BE THE BEST. MY DAUGHTER DOES EVERYTHING ANYBODY ELSE CAN DO , JUST A LITTLE BAD ON COMMUNICATION, BUT HEY ITS ALOT BETTER THAN THE ALTERNATIVE. MY BOYS WERE PUT ON XYPREXIA AND NOT SO GOOD. THEY DONT LIVE WITH ME BUT IM GOING TO SEE WHAT I CAN DO TO CHANGE THE MEDS.THERE IN THERE 30'S. SCHIZOPHRENIA HAS BEEN AROUND BEFORE DRUGS AND PESTICIDES WERE INVENTED , SO I LEAVE THE EXPLANATION UP TO GOD.